The Chemistry and Biology of Glycosaminoglycans

GAGs are polymers of disaccharide building blocks:

The sugar backbone can be sulfated at various positions.  As a result, a simple hexasaccharide can have over 4000 different sulfation sequences!

Distinct sulfation sequences appear to encode the assembly of signaling complexes at the cell membrane.  For example, well-defined GAG sulfation sequences are required for the activation of fibroblast growth factor (FGF) receptors.

The FGF: FGFR complex is one of the rare examples in which the structural determinants of binding are fairly well understood.

A major goal of our laboratory is to develop general methods for the synthesis of defined GAG sequences.  This will allow us to elucidate how distinct sulfation patterns encode the biological functions of GAGs in the brain.

The synthesis of GAGs poses many challenges:

1) Stereocontrolled assembly of alternating galactosamine and glucuronic acid glycosidic linkages (a- versus b- configuration)

 

2) Regiocontrolled installation of a variety of chemical functionalities, including hydroxyl, carboxylate, O-sulfate and N-acetyl groups